Method for preparing quinazolone intermediates



Wm-Msg,

United States Patent 2,715,597 n METHOD non rnnrannsc .QUINAzoLoNE WTERMEDMES t Bernard R. Baker, Nanuet, N. Y., and Francis J. McEvoy,

Nntley, N. J., assignors to American Cyanamid Company, New York, N. Y., a corporation of Maine N Drawing- Application February ,1.2, 19.54,

Serial No. 410,034

13 Claims. (ci. 26e-294.3)

This invention relates to new organic compounds and methods for preparing `the same. `More particularly it relates to an improved synthesis for l-carlbethoxy-Z- (gamma-,bromoacetonyD 3 methoxy-piperidine. New

, intermediates involved in the synthesis and novel methods for their preparation are also included in the scope of `the invention.

l,onyl-3-methoxy-piperidine) is a useful intermediate in Xthe `synthesis of beta-lieto-alkyl-quinazolones which are valu- ,ablein the field ,of dye intermediates and pharmaceuticals.

Hor example, it may be readily converted to the therapeutically valuable S-Tbeta-keto-gamma-(-1-carbethoxy- 31methoxy-2fpiperidyl)propyll -4-quinazolone upon treat- .Jment with sodium methoxide `in methyl alcohol asdisclosedin Patient No. 2,651,632.

,Previously known methods of synthesizing lvcar'bethinvolved the use of diazomethane l,Whichgis toxigexplosive and limited in availability. In View of the importance of this compound as an intermediate for the preparation of valuable therapeutic and .pharmaceutical substances, a simple, yinexpensive and safe method `for `its syntliei,Si{S highly desirable.

These objects are attained by the process of the present invention in which the use of lcliazomethane is avoided.

In accordance with `the process of ,this invention, 1-

fpiperidine is obtained by a method involving a number of v`new `organic lcompounds n V and reactions. The starting `1,1,r1ateriaL 2-methy1-3-pyrd0h1is Converted t0 2-,metl1yl-.3- y methexypyridine Aupon vtreatment withsuitable alkali, 9T i .example an alkaliimetalalwhslate'81191128 Sodium :916th- Qxide, ,sodium ethoxide, potassium methoxide ,or

yethoxide; Aalkali `metal hydroxides such as sodium ,hy-

f droxide,,potassiumhydroxide orflithium hydroxide; alkali i ,metal carbonatos, lsuch as sodium carbonate, lpotassillym carbonate, for 1 lithium Carbonate. yin @the presence fof ,methylpheuylammonum l.chlorisile lfollowed by Lreuxing ,in `a Asuitable y.organic solvent. The ,reaction may jbe l,represented as follows:

i CH3 The temperature during this reaction is critical and should be maintained Within'the range of 120 C. and 180 C. although the reaction e, proceeds smoothly oryvithout a solvent, if one is used it mustbe of an'organic, @sinon-acidic character, such as for example, ;acetoneLdimethylfomam-ide, chloroform, ethyl s acetate, toluene, xylene, chlorobenzene, formamide, ethyleneglycol or others of similar nature.

y The `Znnethyl-3-methoxyfpyridine is ,then treated with an aryl or lower alkyl lithium salt such asphenyl-lithium hor butyl=li`thium, in the presence of an'inert organic `s'ol- "ventsuch as that used in-theGrignard synthesis auf 2,775,597 Patented Dec. 25, 1956 ice for example, ethyl ether or butyl ether. T he intermediate ,n2-lithium methyl-3-methoxy-pyridine is then treated with acetaldehyde to give the compound Z-(b'eta-hydroxypropyl) -3 -methoXy-pyridine N, om-onon-om This compound is then reduced to the piperidine:

OUH:

GHz-CHOH-Cla H by catalytic `reduction in the presence of platinum oxide 1n an acid solution. The presence of the acid aids the reduction of the pyridine ring and increases the speed of hydrogenation. Acids which are useful for this purpose vare `acetic,sulfuric, phosphoric, and others of nature.

The alcohol comprising the side chain of thepiperidine nucleus can next be oxidized to the ,corresponding lis done by catalytic reduction of 2-(-hydroxy-propyl)e3 methoxy-'pyricziine in the presence `of an acid 'such as acetic, propionic, phosphoric or sulfuric. This results in Vfcvrrriwrition of Vthe corresponding pipericline salt is then subjected Without isolation to `liquid-phase oxida- "tion with chromic acid mixture-namely, potassium Adicroma'tle in sulfuric acid, to give 2-ace`tonyl-3-lmethoxy- 'pijperidine The reaction may be represented as follows:

The methyl group on the acetonyl s ide `lchain :is

brom'inated vby the addition of bromine toa solution of `2-acetnyl-3-methoxy-piperidine in water, aqueous acetic acid or glacial acetic acid containing hydrogen bromide. The resultant compound 2-,(gammabromoacetonyl)-3- methoxy-pip'eridine hydrobromide:

QOHS

then readied for condensation with the quinazolone nucleus by protecting the piperidine nitrogen with asuitable blocking group such as the carbethoxy, carbobenzoxy, carboallyloxy, or benzoyl in thepresencevof a weak base, as for example, yan alkali metal carbonate or bicarbonate, such as sodium bicarbonate, Ysotiiumcar- \bonate', potassium bicarbonate, potassium caibcnate,` and others. Convenient reagents for attaching such groups to the nitrogen are ethyl chloroformate, allyl chloroformate, benzyl chloroformate, or benzoyl chloride. The preferred reagent for the reaction in this invention is ethyl chloroformate, which protects the nitrogen with the carbethoxy group. Condensation of the so-obtained l-carbethoxy2(gamma-bromoacetonyl-3-methoxy-piperidine) w wise indicated.

Example I To a solution of 3.8 gms. fof 2-methyl-3-pyridol (LT. Chem. Soc., 71, 297s1) and 1.9 gms. or sodium methoxide in 119 ml. of methanol was added a solution of 6.7 gms. of trim-ethylphenylammonium chloride in ml. of methanol. After 30 minutes the solution was ltered and evaporated to dryness in vacuo. The residue was dissolved in 50 m1. of dimethylform'amide and refluxed for 1 hour.

After addition of 38 m1. of saturated afbsolute alcoholic hydrogen chloride, the solution was evaporated to dryness in vacuo. A solution of Ithe residue in 40 ml. of

. water (was made basic with 40 ml. of 10% sodium hydrox'ide, then extracted twice with chloroform. The combined extracts were evaporated in vacuo leaving 6.2 gms. of an toil. 'llhis oil was dissolved in 30 ml. of ether and shaken with a solution of gms. of cadmium chloride in 40 cc. of Water. The White precipitate of the cadmium chloride complex of 2-methyl-3-methoxy-pyridine 'was collected on a lilter and Washed with Water, then ether.

Y The precipitate ,was suspended in 60 ml. of 'water and 40 ml. of 10% sodi-um hydroxide.

After being heated on a steam-'bath for 1 hour, the mixture was filtered. 'Ilhe filtrate was saturated with salt and extracted with three m-l. portions of chloroform. The combined extracts were dried with magnesium sulfate and evaporated. Distillation of the residue gave 1.25 gms. of Z-methyl-B- methoxylpyridine as a colorless oil, B. P. 80-82 C. (513 mm.). This .compound is somewhat soluble in Water and heptane, but read-ily soluble lin alcohol, ether, chloroform and benzene.

Example II Avmixture of 72.6 gms. of 2methyl-3-pyridol, 726 cc. of dimethylformamide, gms. of sodium methoxide and .12.8 lgms. of tr-imethylphenylammonium chloride was reuxed for 21/2 hours. The reaction mixture was processed. as in Example `1 to give 60.8 gms. of 2-methyl-3- methoxypyridine, B. P. 84-86" C. (15 mm.).

Example III To a solution vof 5.0 gms. of sodium methoxide and 10 gms. of 24methyl-3-pyridol in 50 cc. of methanol was added 17-.6 gms. of tri-methylphenylammfonium chloride in 26 lcc. of methanol. A'fter 15 minutes the mixture was filtered and the :filtrate evaporated to dryness under reduced pressure. The residue was pyrolyzed in a hath at L20-140 C. at a pressure `of 117 mm. until no more product distilled. The distillate, ya mixture of dimethyl- --aniline and 2-methyl-3-methoxy-pyridine, was treated in ether with `aqueous cadmium chloride as in Example I to give 5.5 gms. Iolf 2-methyl-3-methoxy-pyridine, B. P. 82

C. (15mm).

Example IV 'Ilo a solution of 5.0 gms. of sodium methoxide and form, the mixture was filtered. washed with three 80 ml. portions of chloroform which 10 gms. of 2-methyl-3Jpyridol in `50 cc. of methanol was added a solution of 17.6 gms. of trimethylphenylammonium chloride in 26 cc. of methanol. After 15 minutes the mixture =Was filtered and the iltrate evaporated to dryness under reduced pressure. The residue was dissolved in 30 cc. of phenoxy ethanol `and slowly distilled at 17 ml. The distillate (16.1 gm.) B. P. 88-89 C. (17 mm.) wals `a mixture of dimethylaniline and 2-methy1- 3-methoxy-pyridine which was separated with cadmium chloride .as in Example I.

Example V A mixture of 13.1 gms. of 2-rnethyl-3-pyridol, 7.2 gms. of sodium methoxide, 131 ml. of dimethylformamide and 23 gms. of trimethylphenylammonium chloride was refluxed -for 2 hours. After liltration from salt the solution was vacidiiied with ml. of saturated absolute alcoholic hydrogen chloride, then evaporated to dryness in vacuo. The residue was dissolved in 75 ml. of water basied with ml. of 10% sodium hydroxide and extracted with two 100 ml. portions of ether. The cornhined extracts were shaken with 75 ml. of 1.75 M cadmium chloride solution. The pasty mass was treated with 100 ml. of water and 13 gms. of Celite, then liltered. The cadmium chloride complex was mashed with two '50 ml. portions of water iand two 50 ml. portions of ether. -The moist cake was stirred and heated on the steam-bath under a condenser with 300 ml. of 5% sodium hydroxide for 1 |hour. 'Ihe cooled mixture was diluted with 75 ml. of chloroform and filtered. The lilter cake was washed with two 75 ml. portions of chloroform, each washing being used separately to extract the aqueous layer. 'Ilhe combined extracts, dried with magnesium sulfate, were distilled on a steam-bath through a Vigreaux column to remove solvent. Distillation of the residue gave 1l..1 gms. of 2-methyl-3-methoxy-pyridine as a colorless oil, B. P. 80-8\2 C. (114 mm.).

Example VI To a solution of phenyl lithium from 2.8 gms. of lithium and 211 ml. of bromohenzene in ml. of dry ether was added 12.4 gms. of 2methyl3methoxypyri dine dropwise over a period of 15 minutes. The red-brown mixture was reuxed and stirred for 1 hour. Cooled to 5 C. in an ice-salt bath, the mixture was treated by the drop-wise followed by 40 ml. of concentrated hydrochloric acid. The separated aqueous layer was cautiously 'added to a mixture of 44 gms. of sodium carbonate and 60 ml. of water. After addition of 1.20 cc. of chloro- The precipitate Was were used separately to extract the aqueous layer in the .liltrate. 'IIhe combined chloroform extracts, dried with magnesium sul-fate, were evaporated to dryness in vacuo. Dilstillation of the residue gave 7.7 gms. of Z-(-hydroxypropyl)3methoxypyridine as straw colored oil, B. P. 13D-148 C. (10 mm.) Redistillation -gave the pure product, B. P. 143-146 C. (10 mm.). This compound is soluble in water, alcohol, ether or chloroform, but insoluhle in petroleum ether. It forms a hydrochloride salt .from ether as White crystals, M. P. 153-154 C.

Example VII To a retluxed and stirred solution of phenyl lithium from 113 ml. of bromobenzene in 870 cc. of dry ether was added 66.7 gms. of 2 methyl- 3 methoxy-pyridine over a period of forty-tive minutes. After being reuxed an additional hour, the mix-ture was cooled in a nitrogen atmosphere to 5 C. and treated with a solution of 61 ml.

of freshly distilled acetaldehyde in 78 oc. of dry ether at such a rate that the temperature was 5-7" C. (40 min- `Tutos) The reaction mixture was processedas in Example e hasj.

to ga@ sorgissisf natydmxypfapys-memory-pm:- diiieas atyellow dilgfBtP-FIOSLIrzscfj C; min-:L

i solution of ofj ahydroxypropylj)f3-methoxy-pyridinenin -25 m1. of acetic acid ,was shaken lhydrogen. atA 2i-3 atmospheres; and- 70'?a lC; inthe presence To `a solutionl of iidroxypropybrn'ethoicy-piperidliie in 1-8A mlfoflacetic acidfat 80' C. .was

added a solution of 1.35 gms. of chromiumtrioxiile in 1.35' m1. of water portion-'wise over `a period of l0 minutes. The solution was heated on a steam-bath for an additional 30 minutes, then evaporated to `dryness in vacuo. The residue was dissolved in l5 ml. of water, basied with ml. of 50% potassium'hydroxi-de, then extracted .twice with ether.` The combined extracts were dried with magnesium sulfate and evaporated in vacuo (bath 45 C.). Distillation of the residue gave 1.83 gms. of 2-acetony13 methoxy-piperidine as a nearly colorless oil, B. P. 110- 118 C. (15 mm). Thiscompoundis soluble in water,

i alcohol, ether, chloroform or acetic acid, but insoluble A solution .of 24 gms. of Z-(-hydroxypropyl)-3-meth- Oxy-pyridine in 100 ml. of acetic acid was 4shaken Wit-h hydrogen at2-3 atmospheres and 78 C. until reduction was complete' (3 hours). The filtered solutions from two such reductions were combined and evaporated in vacuo to a viscous syrup of 2-(-hydroxypropyD-3-methoxy-piperidine acetate. To a solution of this syrup in 325 ml. of water was added 46 ml. of 96% sulfuric acid dropwise with cooling. Then 41.7 gms. of potassium dichromate was added. yThe temperature was maintained at 30-35 C. by :occasional cooling until the reaction was no longer exothermic (30 minutes).l After standing for 20 hours at room temperature, the solution was filtered from the chromic sulfate crystals. The ltra-te was diluted with 270 ml. of water, then basilied with 390 ml. of 50% potassium hydroxide. The solution was claried by liltration through Celite and extracted with ve 270 ml. portions of ether. The combined extracts, dried with magnesium sulfate, were concentrated in vacuo. Fractional distillation of the residue gave 21.4 gms. 2-.acetony1-3- methoxyapiperidine las a colorless oil, B. P. 68-76 C. (1.1 mm).

Example Xl.

To a solution of 500 mg. of 2-acetonylB-methoxy-piperidine in 4.0 ml. of hydrogen bron-ride in acetic acid w-as added drop-wise a solution of 0.15 cc. of bromine in 0.5 cc. acetic acid. After 2 hours at room temper-alture, the solution was evaporated to dryness in vacuo. The residual 2-(fy-bromoacetonyl)-3-rnethoxypiperidine hydrobromide was dissolved in l0 cc. of chloroform and stirred in an iceabath. After the laddition of l0 ml. of saturated aqueous sodium .bicarbonate and 0.32 cc. of ethyl chlorocarbonate, the mixture was stirred at 0 C. for 30 minutes. After the addition of 3 ml. of saturated aqueous sodium bicarbonate and 0.32 ml. of ethyl chlorocarbonate, the mixture was stirred at 0 C. for an additional 30 minutes. The separated chloroform layer was washed withA two: 101ml.i portions'ot IN1 hydrochloric acid; Dried Withnagneiumsliate, the` solution was evaporated to dryness in vacuo leaving 910 mg. of I-CarbethoxyQZ-(fy bromoacetonyl)-Sunethxyapiperidine as a gum.

p Example XII 9110' Ing. of,pLcarbethoxy-Zr('yabromoacetonyl)-3-inethf oxy-piperidine was condensed with 410 mg. o f 4quinazolone as described `in U. S. Patent No. 2,651,632. A yield ofY 380 lmg. :0123-[13#lieto-fw(1-canbethoxy-3-n1ethoxyi Zapiperidyl)-propyl]4quinazolone was obtained, M. P. `13J6 "4"Ct Y.

1. A method which comprises the steps of treating 2- methyl-.Sv-pyridol *withk sodium methoxide and trimethylphenylammonium p chloride at a temperature of from abrout.12v0 C. to about 18.0` C. in the presence of a nonacidic` organic solvent` to obtain:

O CH3 N/ CHZ-OHOH-OH:

reducing said compound with vhydrogen in the presence of platinum oxide catalyst to obtain:

` O CH3 i N CHr-CHOH-CHa oxidizing said compound under strong oxidizing conyditions to obtain: Y

GHz-(HJ-OH: o brominating said compound to obtain:

0 CH: lCHz-(Hl-CHZBI' HBr and contacting said product with ethyl chlorocarbonate to obtain:

omi bromoacctonyl) -3-methoxy-piperdine,` f whicha,l e comprises the Astep of reacting 2 lithium methyl 3 lmethoxypyridine with acetaldehyde. a

5. Ina method for preparing l-'carbethoxy-Z-(gamma bromoacetonyl)-3-methoxy-piperidine, which comprises the step of reducing 2-(betahydr0xypropy1)-3-methoxy-` pyridine with hydrogen and platinum oxide` catalyst in the presence of 'a strong acid.

6. VIn a method for preparing 1carbethoxy2 (gamma bromoacetonyl) 3 methoxy-piperidine, which comprises the step of oxidizing Z-(beta-hydroxy-propyl)-3- methoxy-pyridine which comprises treating said compound with chromium trioxide in the presence :ofaweak V .7. 'In a method for preparingv1-carbethoxy2-(gammabromoacetonyl) 3 vmethoXy-piperidine, which comprises the steps-'of treating 2 (beta-hydroXy-propy1)3 methoXy-pyridine with hydrogen and oxidizing the resultant compound with potassium dichromate in the pres ence of a strong acid.

8. In a method for preparing 1-carbethoXy-2-(gammabromoacetonyl) 3-metho'Xy-piper'idine, which comprises the step oftreating 2,-acet0nyl-3-methoxyfpiperidine with hydrogen bromide `in the presence `of a member selected s 8 from thef'group ,consisting'of Water, glacial acetic acid and mixtures .of Waterfand acetic acid, followed by the drop-wise addition 0f bromne.

9. In a method for preparing 1carbethoXy-2-(gamma bromoacetonyl) -E-methoxy-piperidine, which comprises the step of treating 2 (gamma-bromoacetonyl) 3 methoXy-piperidine hydrobromide with ethyl chlorocarbonate underweakly basic conditions.

110. The compound 2 (beta-hydroxy-propyl) 3 methoxypyridine.-' Y' v 11. The compound 2 (beta-hydroxy-propyl) 3 methoxy-piperidine'.

12.'The compound 2-acetonyl-S-methoXy-piperidine. v 13. The compound 2 (gamma-bromoacetonyl) 3 methoxy-piperidine hydrobromide.

References Cited in the le of this patent FOREIGNpPATENTs y 125,690 -Aus'tria i Nov. 2s, 1931 lOTHER REFERENCES I l\ /Ia14'ionv et al Jour. Am. Chem. Soc., vol.` 71, pp. 34o2fo4 (1949). .i y 

1. A METHOD WHICH COMPRISES THE STEPS OF TREATING 2METHYL-3-PYRIDOL WITH SODIUM METHOXIDE AND TRIMETHYLPHENYLAMMONIUM CHLORIDE AT A TEMPERATURE OF FROM ABOUT 120* C. TO ABOUT 180* C. IN THE PRESENCE OF A NONACIDIC ORGANIC SOLVENT TO OBTAIN: 